This SCOR grant addresses the syndromes related to sleep-disordered breathing with the view that pathogenesis and ultimate control requires a detailed understanding of metabolic, neurophysiologic, and physiologic featrues of apnea-disturbed sleep and hypoxia. We will address how the host response to sleep apneic events results over time in the cardiovascular, respiratory, neuropsychologic, and behavioral problems attributed to sleep apnea. To achieve these aims, we propose six interrelated projects that examine, from multiple perspectives and over time, how sleep apnea, hypoxia, metabolic and growth regulatory factors, and co-morbidity (hypertension, obesity, glucose intolerance, alcohol, and other disease) act and interact to produce symptomatic disease and/or influence treatment outcome. Project 1 examines the role of hypoxia in the incidence of and mechanisms for insulin resistance as common ground for associations between sleep apnea and cardiovascular morbidity. Project 2 will address the distribution of central serotonin neurotransmitter heterogeneity in relation to respiratory control and apneas before and after treatment in patients with sleep apnea. Project 3 focuses on pharyngeal muscles and hypoxia and the potential role of potassium ion channels in determining muscle tension and fatigue. Project 4 is directed at the mechanisms and consequences of brain vascular adaptations to hypoxia. Project 5 systematically describes the distribution of neuropsychologic deficits in patients in relation to comorbidity before and after therapy. Project 6 manipulates and defines factors such as alcohol, hypoxia, and length of illness that modify sleep, alertness, and/or cognitive performance in patients with sleep apnea. Two cores provide administrative and biometrics support for all projects. This interdisciplinary approach will provide new information on the impact of sleep apnea on cellular and organ systems and provide information necessary to understand the need for therapy and avenues for prevention of sleep-disordered breathing.